Infiltrative gliomas are the most common malignancies of the central nervous system. Some low-grade gliomas progress to higher-grade gliomas, including lethal glioblastoma multiforme (GBM) for which conventional therapies are essentially palliative. Novel molecular-targeted therapies and molecular-based classifications are within reach of 21st century cancer medicine. However, the understanding of gliomas at the genetic level is limited, and the molecular mechanisms underlying glioma initiation and progression are largely unknown. With the goal of improving our understanding of these mechanisms, we recently sequenced 20,361 protein coding genes in 22 GBMs and identified frequent somatic mutations in NADP+dependent isocitrate dehydrogenase 1 (IDH1). We then found mutations at the R132 residue of IDH1 or at the analogous R172 residue of the closely related IDH2 in 70%-100% of WHO grade II and grade III astrocytomas and oligodendrogliomas, as well as in secondary GBMs (WHO grade IV). Furthermore, we showed that IDH1 and IDH2 mutations marked a relatively large subgroup of gliomas with a distinct pattern of alterations in other genes and associated with distinct clinical features. IDH mutations appear to play a central role in gliomagenesis, and their study may provide opportunities to improve diagnosis and treatment of gliomas. However, the functional effects of the IDH mutations on glioma behaviors and cell growth remain entirely unknown, the precise molecular mechanisms by which IDH mutations are involved in gliomagenesis are not fully understood, and importantly, the diagnostic and prognostic value of IDH mutations still needs to be evaluated. Our long-term goal is to develop a novel molecular-based glioma classification system and a targeted therapy on the basis of IDH1 and IDH2 mutations and the involved oncogenic pathways. The objective of this application is to pursue that goal, by determining the impact of IDH mutations on glioma cellular biology, identifying the molecular mechanisms by which mutant IDH acts to confer growth or survival advantages to glioma cells and by evaluating IDH mutation status as a diagnostic test to aid with subclassification of gliomas. To test our central hypothesis that IDH1 and IDH2 play a fundamental role in glioma pathogenesis, we will pursue the following specific aims: 1. To determine the effects of IDH mutation on the biology of glioma cells and their putative precursors. 2. To determine the molecular mechanisms underlying the biology of IDH-mutated glioma. 3. To determine the biological basis for, and predictive value of, IDH mutation status in glioma. PUBLIC HEALTH RELAVANCE: a better understanding of the pathological roles and mechanisms of mutant IDH1 and IDH2 on glioma pathogenesis will provide a molecular tool to help improve the notoriously difficult and subjective classification of gliomas based on histopathologic criteria, and may contribute significantly to the molecular therapeutic intervention in this frequently lethal cancer. PUBLIC HEALTH RELEVANCE: This grant application aims to contribute significantly to a fundamental understanding of the pathogenic and functional roles of IDH1 and IDH2 in glioma cellular biology and pathogenesis as well as of their diagnostic and prognostic values. This contribution is significant, therefore, because it is expected to provide the knowledge of this new pathway for glioma pathogenesis, as well as provide immediate clinical implications for using IDH1 and IDH2 mutation as a novel molecular tool to help improve the difficult classification of gliomas and for the design of future clinical trials.